World Without AIDS: Update on HIV Cure and Vaccine Research

Progress So Far

With over 30 HIV antiretrovirals and 11 prevention strategies, we have been able to think aspirationally about getting to a world without HIV/AIDS. Achieving that goal is realistic, but still requires a lot of research. Anthony Fauci, M.D., director of U.S. National Institute of Allergy and Infectious Diseases (NIAID), discussed the critical challenges that remain, including our mixed progress toward a cure or vaccine, while speaking at the 20th International AIDS Conference (AIDS 2014) in Melbourne, Australia.

According to the 2014 UNAIDS Gap Report, we now have 35 million people living with HIV, with 2.1 million new HIV infections in 2013 (down 38% since 2001) and 1.5 million AIDS deaths in 2013 (down 35% since 2005). While incidence and mortality numbers have lowered significantly, they could be lowered completely with the discovery of an HIV cure.

A cure is defined as the "permanent remission of disease following cessation of treatment," according to Fauci. With infectious diseases, this has traditionally meant the eradication of the microbe; however, with certain diseases, such as cancers, it means the absence of relapse for life or a defined period of time. Regardless, in order to prove an HIV cure, we need to be able to identify biomarkers of the HIV reservoir, which is notoriously difficult to locate or measure.

Moreover, with HIV, we simply do not know how long the virus needs to be in remission after stopping antiretroviral therapy (ART) before we can confidently consider an HIV-positive person to be "cured."

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The Role of the HIV Reservoir

To help us better understand the HIV reservoir, Fauci broke it down into two buckets: qualitative and quantitative aspects. Qualitatively, the reservoir can be categorized by "body compartment type," "cell type" and "status of virus."

The "status of virus" can either be "defective" or "replication competent," the latter of which is actually a very small percentage.

Quantitatively, the amount of time between initial infection and beginning ART determines the baseline size of the HIV reservoir. In fact, the reservoir can form earlier than HIV viremia can even be detected. All of these factors confound how we look at the HIV reservoir, according to Fauci.

In addition, the reservoir is very persistent, in that even after years of treatment and viral suppression, the reservoir remains. It usually only takes a couple of weeks after discontinuation of ART for the virus to rebound.

Addressing the HIV Reservoir: Eradication

To deal with the reservoir, there are two possible ways that many researchers have been pursuing: eradicating the reservoir or controlling viral rebound with sustained virologic remission.

Eradication strategies include:

Flushing the virus out by activating the latently infected cells, also known as "shock and kill." So far, researchers have been able to "shock," but not "kill."

Directing immunotoxic therapy at the reservoir, which gets rid of some cells, but not all.

Stem-cell transplants with CD4 cells that have a key CCR5 mutation -- the deletion of a specific gene -- which so far has only worked in one patient, Timothy Brown. Stem-cell transplants involving CD4 cells without the CCR5 mutation, as seen in the Boston patients, seemed successful initially, but months after stopping treatment the virus rebounded.

Gene therapy, using zinc finger nucleases (ZFNs) to modify the CCR5 receptor. This has shown some promise, but research is still in early stages.

Beyond the Mississippi Child

Treating HIV as early as possible still seems to be one of the keys to eradication, as seen with the "Mississippi Child." Even though it was disappointing that the child's virus rebounded, the fact that the child appeared to remain virus-free for so long is still a promising development.

The case has also raised some critical questions, including: What mechanism kept the virus from rebounding for 27 months without treatment? What triggered the rebound? From what cell type and body compartment type did the virus rebound?

To try to answer these questions and others, IMPAACT Study P1115 will attempt to ethically recreate the "Mississippi Child" scenario, by identifying and treating HIV-positive infants within 48 hours after birth. According to Fauci, sustained virologic remission in babies could be translated to the same outcome in adults, as long as they share potential commonalities -- e.g., early initiation of ART, favorable quantitative and qualitative aspects of the HIV reservoir, and relative preservation of immune function.

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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

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